Jeffrey Blake

Pulmonary arterial hypertension (PAH) is a lethal disease that ultimately culminates in right ventricular (RV) failure, due to remodeling of pulmonary vasculature that increases RV workload. PAH is a disease characterized by systemic metabolic defects including insulin resistance and disrupted lipid degradation in liver dysfunction, and these metabolic pathways haven’t been targeted for therapeutic purposes. However, the role of amino acid metabolism in PAH pathology is largely unexplored, and this important knowledge gap was directly examined in this proposal. Literature search of human PAH metabolomics studies was conducted in the liver. For rodent studies, male Sprague Dawley rats were divided into three groups: control (saline injection), monocrotaline (MCT) vehicle (MCT-V), or MCT-BT2, a small molecule inducer of BCAA catabolism. BT2 was administered at 20 mg/kg/day. A low BCAA dietary intervention was implemented, with male Sprague Dawley rats divided into two groups: MCT-standard chow diet and MCT-low BCAA diet. To assess exercise capacity, rodents underwent a maximal exercise testing protocol before echocardiographic and hemodynamic assessments of PAH. BCAAs are elevated in human PAH and reduction of BCAAs via small molecule activation of BCAA catabolism in a pro-inflammatory phenotype in the liver which comprises its metabolic activities and liver function. BT2 treatment improved exercise performance, reduced PA pressures, and augmented RV function. Moreover, the MCT-BT2 group possessed a distinct liver proteomic signature with changes in inflammatory and metabolic pathways accompanied by increased nuclear size in hepatocytes. Finally, the low BCAA diet intervention modestly combatted PAH severity.